Cytosolic calcium plays a leading role in the control of neuronal excitability, plasticity and survival. This work aims to experimentally assess the possibility that lipid rafts of the plasma membrane can provide a structural platform for a faster and tighter functional coupling between calcium and nitric-oxide signaling in neurons. Using primary cerebellar granule neurons (CGN) in culture this hypothesis has been experimentally assessed with fluorescence resonance energy transfer imaging, preparations of lipid rafts-enriched membrane fragments and western blotting. The results obtained in this work demonstrated that major calcium entry systems of the plasma membrane of CGN (L-type calcium channels and N-methyl-D-aspartate receptors) and nitric-oxide synthase are separated by less than 80 nm from each other within lipid rafts-associated sub-microdomains, suggesting a new role of lipid rafts as neuronal calcium/redox nano-transducers. (C) 2012 Elsevier Inc. All rights reserved.